title: Histone deacetylase inhibition attenuates diabetes-associated kidney growth: potential role for epigenetic modification of the epidermal growth factor receptor.
abstract: Clinical trials and experimental studies have highlighted the importance of epigenetic processes in the development of diabetic complications. One of the earliest features of diabetic nephropathy is renal enlargement. The epidermal growth factor (EGF) has a pivotal role in the development of diabetic nephromegaly and transactivation of its receptor has been implicated in the pathogenesis of later-stage disease. As EGF signaling is altered by the acetylation status of histone proteins, we measured the effects of the histone deacetylase (HDAC) inhibitor, vorinostat, in mediating renal enlargement in diabetes focusing on the EGF-EGF receptor (EGFR) axis. In cultured proximal tubule (normal rat kidney) cells, vorinostat treatment reduced EGFR protein and mRNA, and attenuated cellular proliferation. Within 72 h of diabetes induction with streptozotocin, urinary EGF excretion was increased approximately threefold and was unaffected by vorinostat, even though the kidneys of vorinostat-treated diabetic rats had reduced tubular epithelial cell proliferation. Daily treatment of diabetic rats with vorinostat for 4 weeks blunted renal growth and glomerular hypertrophy. Thus, early renal changes in diabetes are amenable to epigenetic intervention. Attenuating effects of HDAC inhibition, although multifactorial, are likely to be mediated in part through downregulation of the EGFR.
authors.affiliation: Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
authors.forename: Qingling
authors.initials: Q
authors.lastname: Huang
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Advani
authors.forename: Kodie
authors.initials: K
authors.lastname: Lee
authors.forename: Darren A
authors.initials: DA
authors.lastname: Yuen
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D006984:Hypertrophy; D007678:Kidney Glomerulus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D000077337:Vorinostat; C483803:Egfr protein, rat; D066246:ErbB Receptors